Installation of -SO2F groups onto primary amides

  1. Jing Liu1,
  2. Shi-Meng Wang1,
  3. Njud S. Alharbi2 and
  4. Hua-Li Qin1ORCID Logo

1State Key Laboratory of Silicate Materials for Architectures; School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, China
2Biotechnology Research group, Deportment of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia

  1. Corresponding author email

Associate Editor: T. P. Yoon
Beilstein J. Org. Chem. 2019, 15, 1907–1912. doi:10.3762/bjoc.15.186
Received 29 May 2019, Accepted 31 Jul 2019, Published 09 Aug 2019

A non-peer-reviewed version of this article has been previously published as a preprint doi:10.3762/bxiv.2019.33.v1

Abstract

A protocol of SO2F2-mediated installation of sulfonyl fluoride onto primary amides has been developed providing a new portal to sulfur(VI) fluoride exchange (SuFEx) click chemistry. The generated molecules contain pharmaceutically important amide and -SO2F moieties for application in the discovery of new therapeutics.

Keywords: N-fluorosulfonyl amides; primary amides; sulfuryl fluoride (SO2F2)

Introduction

Sulfur(VI) fluoride exchange (SuFEx) is a new class of click chemistry developed by Sharpless and co-workers in 2014, for creating molecular connections based on the unique stability–reactivity pattern of the S(VI)–F bond with reliability and efficiency, which has been widely applied in organic synthesis, chemical biology and drug discovery [1-19]. Among all the developed S(VI)–F species, sulfonyl fluoride (RSO2F) was specifically recognized as unique scaffold for covalent protein inhibitors and biological probes with the affinity-driven activation for forming covalent linkages with the amino acid residues of protein binding sites (Figure 1) [20]. The smallest member of this family, methyl sulfonyl fluoride (MSF), is known as a selective and irreversible inhibitor of acetylcholinesterase (AChE) [21,22]. The sulfonyl fluoride inhibitors NSC 127755 was found for specifically modifying tyrosine-31 of DHFR in chicken liver [23]. The nucleotide-derived probe 5’-(para-fluorosulfonylbenzoyl)adenosine (5’-FSBA) was used for labelling the second nucleotide binding site, the adenine nucleotide regulatory site [24]. In addition, aryl fluorosulfates have also been widely applied as sustainable alternative to aryl halides in coupling reactions and as potential covalent probes in protein profiling [14,25-28].

[1860-5397-15-186-1]

Figure 1: Representative sulfonyl fluoride compounds applied in medicinal chemistry and chemical biology.

Phenols (or alcohols) and amines as the most common nucleophiles have been found to react with different S(VI) connectors (SO2F2, CH2=CH-SO2F, SOF4 etc.) to provide diversified sulfonyl fluoride derivatives. The reactions of phenols (or alcohols) with SO2F2 [29] or the fluorosulfuryl imidazolium salt were developed for mild and effective formation of the corresponding fluorosulfates to act as biological probes in chemical proteomics studies (Scheme 1, (1)) [1,30]. On the other hand, the reactions of aliphatic or aromatic amines with SO2F2 or the fluorosulfurylimidazolium salt have been achieved for assembly of N-sulfonyl fluorides [1,30], which have served as important active precursors for the development of noncovalent inhibitors (Scheme 1, (1)) [1,30,31]. Amides are the key connections in proteins, amides, and a vast number of synthetic structures, such as polymers, biologically active compounds and pharmaceutical products [32-35]. However, the installation of sulfonyl fluoride (SO2F) onto nitrogen atoms of amides has not been achieved, which, if accomplished, would provide a very important class of sulfonyl fluorides, namely, N-fluorosulfonyl amides, for the development of potential covalent inhibitors [1-24]. The Roesky group described a pioneering protocol for the synthesis of N-fluorosulfonyl amides from fluorosulfonyl isocyanate (Scheme 1, (2)) [36]. The available procedures for the preparation of N-fluorosulfonyl amides are very limited which relied on using either the isocyanate approach, or the amidosulfofluoride (FSO2NH2) (Scheme 1, (2)) [37-39]. Therefore, the development of a new method for the assembly of N-fluorosulfonyl amides from cheap and abundant reagent is highly desirable. Herein, we report the first, to the best of our knowledge, SO2F2-mediated N-fluorosulfonylation [40-42] of amides by using DBU as base for the constructions of a series N-fluorosulfonyl amides (Scheme 1b).

[1860-5397-15-186-i1]

Scheme 1: Synthesis background of N-fluorosulfonyl amides and fluorosulfates.

Results and Discussions

Initially, benzamide (1a) was selected as model substrate to test the feasibility of this proposed N-fluorosulfonylation reaction in the presence of Cs2CO3 in DMSO under SO2F2 atmosphere (balloon) at 50 °C, and excitingly, the desired product benzoylsulfamoyl fluoride (2a) was obtained in 25% yield (Table 1, entry 1). Encouraged by this preliminary success, several common bases were evaluated, among which, 1,8-diazabicycloundec-7-ene (DBU) catalysed the proposed transformation most effectively to provide the desired product 2a in nearly quantitative yield (Table 1, entries 2–7). Subsequently, different solvents were screened (Table 1, entries 5, 8–12) and DMSO was found to be the best option. Decreasing the temperature from 50 °C to 40 °C or even room temperature, or cutting down the amount of DBU to 4 equivalents resulted in decreased yields (Table 1, entries 13–15).

Table 1: Optimization of the reaction conditions.a

[Graphic 1]
Entry Base Solvent Temp. (°C) Yield (2a, %)b
1 Cs2CO3 DMSO 50 25
2 K2CO3 DMSO 50 13
3 KOH DMSO 50 19
4 NaOH DMSO 50 15
5 DBU DMSO 50 99
6 Et3N DMSO 50
7 DIPEA DMSO 50
8 DBU NMP 50 81
9 DBU MeCN 50 75
10 DBU toluene 50 87
11 DBU dioxane 50 60
12 DBU THF 50 79
13 DBU DMSO 40 82
14 DBU DMSO R.T. 51
15c DBU DMSO 50 69

aReaction conditions: benzamide (1a, 1.0 mmol, 1.0 equiv), DBU (5.0 equiv), and DMSO (1.0 mL) stirred with a SO2F2 balloon for 12 h. bIsolated yield. c4 equiv of DBU was used.

With the optimized conditions in hand, we next turned our efforts to investigate the scope of substrates. Under the standard conditions, a variety of substituted amides were examined which were smoothly converted to their corresponding substituted benzoylsulfamoyl fluoride derivatives (Scheme 2) in moderate to excellent isolated yields. Both electron-withdrawing groups, such as halogen atoms (1bd, 1j, 1m, and 1n), NO2 (1e, 1k) and CF3 (1f), and electron-donating groups, such as Me (1g, 1l, and 1o), tert-butyl (1h) and 2-naphthyl (1i) on the aromatic rings, were well tolerated under the optimized conditions. It was worth noting that not only para- (1bh) but also meta- (1jl) and ortho- (1mo) substituted benzamides afforded the desired products in generally good yields. Arylcarboxylic amides (1p and 1q) bearing bis-substitutions also behaved well under the standard conditions. Heterocyclic aromatic carboxylic amides (1ru) were well-tolerated and afforded the target products in 56–90% yields. In addition, alkyl carboxylic amides were also smoothly transformed into the corresponding products (2vz). However, primary amides bearing an amino group or a phenolic hydroxy group were not successfully converted to the corresponding N-fluorosulfonyl amides and only a mixture of undesired products were observed.

[1860-5397-15-186-i2]

Scheme 2: Screening of the substrate scope of amides. Reaction conditions: a mixture of amides 1 (1.0 mmol), DBU (5.0 mmol, 5.0 equiv), and DMSO (1.0 mL) was added to a reaction flask before SO2F2 was introduced into the stirred reaction mixture by slowly bubbling from a balloon, and the mixture was allowed to stir at 50 °C for 12 h. Isolated yields. a50 °C, 18 h.

Interestingly, during the work-up process of drying 2e with Na2SO4, a colourless crystal 4e was observed and its structure was confirmed by XRD analysis (Scheme 3). We speculate that the tautomerism of amides [43] may occur in the reaction process and the tautomer 3e could react with Na2SO4 to generate 4e, which indicated that N–H connected with two electron-withdrawing groups (carbonyl, and SO2F) can behave as an acid to donate a proton for chemical transformations. This property of fluorosulfonyl amides 2 with nucleophilicity may attract significant attention for further applications.

[1860-5397-15-186-i3]

Scheme 3: Amide resonance model and X-ray single crystal structure of 4e (CCDC 1906002).

As depicted in Scheme 4, a plausible reaction mechanism is proposed for SO2F2-mediated transformation of amides to N-fluorosulfonyl amides. The reaction was initiated by the deprotonation of amide 1 with the base (DBU) to generate an intermediate A, which subsequently went through a SuFEx process with SO2F2 to deliver the final product 2.

[1860-5397-15-186-i4]

Scheme 4: The proposed reaction mechanism.

Conclusion

In conclusion, we have developed a novel method for N-fluorosulfonylation of amides. This simple, convenient, and mild protocol provides a portal to a class of novel sulfonyl fluorides for SuFEx click chemistry with great potential to be applied in the development of covalent inhibitors. Further studies of this class of molecules in chemical biology and drug discovery are underway in our laboratory.

Supporting Information

Supporting Information File 1: Experimental part.
Format: PDF Size: 1.7 MB Download
Supporting Information File 2: Crystallographic information file of 4e.
Format: CIF Size: 14.6 KB Download
Supporting Information File 3: Checkcif file of 4e.
Format: PDF Size: 245.1 KB Download

Acknowledgements

We are grateful to the National Natural Science Foundation of China (Grant No. 21772150), the Wuhan applied fundamental research plan of Wuhan Science and Technology Bureau (grant NO. 2017060201010216), the 111 Project (No. B18038) and Wuhan University of Technology for the financial support.

Conflicts of Interest

The authors declare no competing financial interest.

References

  1. Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2014, 53, 9430–9448. doi:10.1002/anie.201309399
    Angew. Chem. 2014, 126, 9584–9602. doi:10.1002/ange.201309399
    Return to citation in text: [1] [2] [3] [4] [5]
  2. Wang, H.; Zhou, F.; Ren, G.; Zheng, Q.; Chen, H.; Gao, B.; Klivansky, L.; Liu, Y.; Wu, B.; Xu, Q.; Lu, J.; Sharpless, K. B.; Wu, P. Angew. Chem., Int. Ed. 2017, 56, 11203–11208. doi:10.1002/anie.201701160
    Angew. Chem. 2017, 129, 11355–11360. doi:10.1002/ange.201701160
    Return to citation in text: [1] [2]
  3. Gao, B.; Zhang, L.; Zheng, Q.; Zhou, F.; Klivansky, L. M.; Lu, J.; Liu, Y.; Dong, J.; Wu, P.; Sharpless, K. B. Nat. Chem. 2017, 9, 1083–1088. doi:10.1038/nchem.2796
    Return to citation in text: [1] [2]
  4. Liu, Z.; Li, J.; Li, S.; Li, G.; Sharpless, K. B.; Wu, P. J. Am. Chem. Soc. 2018, 140, 2919–2925. doi:10.1021/jacs.7b12788
    Return to citation in text: [1] [2]
  5. Qin, H.-L.; Zheng, Q.; Bare, G. A. L.; Wu, P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2016, 55, 14155–14158. doi:10.1002/anie.201608807
    Angew. Chem. 2016, 128, 14361–14364. doi:10.1002/ange.201608807
    Return to citation in text: [1] [2]
  6. Zha, G.-F.; Zheng, Q.; Leng, J.; Wu, P.; Qin, H.-L.; Sharpless, K. B. Angew. Chem., Int. Ed. 2017, 56, 4849–4852. doi:10.1002/anie.201701162
    Angew. Chem. 2017, 129, 4927–4930. doi:10.1002/ange.201701162
    Return to citation in text: [1] [2]
  7. Schimler, S. D.; Cismesia, M. A.; Hanley, P. S.; Froese, R. D. J.; Jansma, M. J.; Bland, D. C.; Sanford, M. S. J. Am. Chem. Soc. 2017, 139, 1452–1455. doi:10.1021/jacs.6b12911
    Return to citation in text: [1] [2]
  8. Epifanov, M.; Foth, P. J.; Gu, F.; Barrillon, C.; Kanani, S. S.; Higman, C. S.; Hein, J. E.; Sammis, G. M. J. Am. Chem. Soc. 2018, 140, 16464–16468. doi:10.1021/jacs.8b11309
    Return to citation in text: [1] [2]
  9. Liang, Q.; Xing, P.; Huang, Z.; Dong, J.; Sharpless, K. B.; Li, X.; Jiang, B. Org. Lett. 2015, 17, 1942–1945. doi:10.1021/acs.orglett.5b00654
    Return to citation in text: [1] [2]
  10. Zhang, E.; Tang, J.; Li, S.; Wu, P.; Moses, J. E.; Sharpless, K. B. Chem. – Eur. J. 2016, 22, 5692–5697. doi:10.1002/chem.201600167
    Return to citation in text: [1] [2]
  11. Fang, W.-Y.; Leng, J.; Qin, H.-L. Chem. – Asian J. 2017, 12, 2323–2331. doi:10.1002/asia.201700891
    Return to citation in text: [1] [2]
  12. Wang, X.-Y.; Leng, J.; Wang, S.-M.; Asiri, A. M.; Marwani, H. M.; Qin, H.-L. Tetrahedron Lett. 2017, 58, 2340–2343. doi:10.1016/j.tetlet.2017.04.070
    Return to citation in text: [1] [2]
  13. Fang, W.-Y.; Huang, Y.-M.; Leng, J.; Qin, H.-L. Asian J. Org. Chem. 2018, 7, 751–756. doi:10.1002/ajoc.201800037
    Return to citation in text: [1] [2]
  14. Revathi, L.; Ravindar, L.; Leng, J.; Rakesh, K. P.; Qin, H.-L. Asian J. Org. Chem. 2018, 7, 662–682. doi:10.1002/ajoc.201700591
    Return to citation in text: [1] [2] [3]
  15. Zhao, C.; Fang, W.-Y.; Rakesh, K. P.; Qin, H.-L. Org. Chem. Front. 2018, 5, 1835–1839. doi:10.1039/c8qo00295a
    Return to citation in text: [1] [2]
  16. Zha, G.-F.; Fang, W.-Y.; Li, Y.-G.; Leng, J.; Chen, X.; Qin, H.-L. J. Am. Chem. Soc. 2018, 140, 17666–17673. doi:10.1021/jacs.8b10069
    Return to citation in text: [1] [2]
  17. Zhao, C.; Zha, G.-F.; Fang, W.-Y.; Rakesh, K. P.; Qin, H.-L. Eur. J. Org. Chem. 2019, 1801–1807. doi:10.1002/ejoc.201801888
    Return to citation in text: [1] [2]
  18. Zhang, X.; Rakesh, K. P.; Qin, H.-L. Chem. Commun. 2019, 55, 2845–2848. doi:10.1039/c8cc09693g
    Return to citation in text: [1] [2]
  19. Wang, S.-M.; Zhao, C.; Zhang, X.; Qin, H.-L. Org. Biomol. Chem. 2019, 17, 4087–4101. doi:10.1039/c9ob00699k
    Return to citation in text: [1] [2]
  20. Narayanan, A.; Jones, L. H. Chem. Sci. 2015, 6, 2650–2659. doi:10.1039/c5sc00408j
    Return to citation in text: [1] [2]
  21. Moss, D. E.; Berlanga, P.; Hagan, M. M.; Sandoval, H.; Ishida, C. Alzheimer Dis. Assoc. Disord. 1999, 13, 20–25. doi:10.1097/00002093-199903000-00003
    Return to citation in text: [1] [2]
  22. Kitz, R.; Wilson, I. B. J. Biol. Chem. 1962, 237, 3245–3249.
    Return to citation in text: [1] [2]
  23. Kumar, A. A.; Mangum, J. H.; Blankenship, D. T.; Freisheim, J. H. J. Biol. Chem. 1981, 256, 8970–8976.
    Return to citation in text: [1] [2]
  24. Esch, F. S.; Allison, W. S. J. Biol. Chem. 1978, 253, 6100–6106.
    Return to citation in text: [1] [2]
  25. Hanley, P. S.; Clark, T. P.; Krasovskiy, A. L.; Ober, M. S.; O’Brien, J. P.; Staton, T. S. ACS Catal. 2016, 6, 3515–3519. doi:10.1021/acscatal.6b00865
    Return to citation in text: [1]
  26. Mortenson, D. E.; Brighty, G. J.; Plate, L.; Bare, G.; Chen, W.; Li, S.; Wang, H.; Cravatt, B. F.; Forli, S.; Powers, E. T.; Sharpless, K. B.; Wilson, I. A.; Kelly, J. W. J. Am. Chem. Soc. 2018, 140, 200–210. doi:10.1021/jacs.7b08366
    Return to citation in text: [1]
  27. Chen, W.; Dong, J.; Plate, L.; Mortenson, D. E.; Brighty, G. J.; Li, S.; Liu, Y.; Galmozzi, A.; Lee, P. S.; Hulce, J. J.; Cravatt, B. F.; Saez, E.; Powers, E. T.; Wilson, I. A.; Sharpless, K. B.; Kelly, J. W. J. Am. Chem. Soc. 2016, 138, 7353–7364. doi:10.1021/jacs.6b02960
    Return to citation in text: [1]
  28. Gilles, P.; Veryser, C.; Vangrunderbeeck, S.; Ceusters, S.; Van Meervelt, L.; De Borggraeve, W. M. J. Org. Chem. 2019, 84, 1070–1078. doi:10.1021/acs.joc.8b02785
    Return to citation in text: [1]
  29. Sulbaek Andersen, M. P.; Blake, D. R.; Rowland, F. S.; Hurley, M. D.; Wallington, T. J. Environ. Sci. Technol. 2009, 43, 1067–1070. doi:10.1021/es802439f
    Return to citation in text: [1]
  30. Guo, T.; Meng, G.; Zhan, X.; Yang, Q.; Ma, T.; Xu, L.; Sharpless, K. B.; Dong, J. Angew. Chem., Int. Ed. 2018, 57, 2605–2610. doi:10.1002/anie.201712429
    Angew. Chem. 2018, 130, 2635–2640. doi:10.1002/ange.201712429
    Return to citation in text: [1] [2] [3]
  31. Spillane, W.; Malaubier, J.-B. Chem. Rev. 2014, 114, 2507–2586. doi:10.1021/cr400230c
    Return to citation in text: [1]
  32. Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage: Structural Significance in Chemistry, Biochemistry and Materials Science; Wiley-Interscience: Hoboken, NJ, 2000.
    Return to citation in text: [1]
  33. Wieland, T.; Bodanszky, M. The World of Peptides: A Brief History of Peptide Chemistry; Springer-Verlag: New York, 1991.
    Return to citation in text: [1]
  34. de Figueiredo, R. M.; Suppo, J.-S.; Campagne, J.-M. Chem. Rev. 2016, 116, 12029–12122. doi:10.1021/acs.chemrev.6b00237
    Return to citation in text: [1]
  35. Crespo, L.; Sanclimens, G.; Pons, M.; Giralt, E.; Royo, M.; Albericio, F. Chem. Rev. 2005, 105, 1663–1682. doi:10.1021/cr030449l
    Return to citation in text: [1]
  36. Roesky, H. W.; Giere, H.-H. Chem. Ber. 1969, 102, 3707–3712. doi:10.1002/cber.19691021112
    Return to citation in text: [1]
  37. Clauβ, K.; Friedrich, H.-J.; Jensen, H. Justus Liebigs Ann. Chem. 1974, 561–592. doi:10.1002/jlac.197419740404
    Return to citation in text: [1]
  38. Pietsch, H.; Clauss, K.; Jensen, H.; Schmidt, E. Verfahren Zur Herstellung Von Acetoacetamid-N-sulfofluorid. Ger. Pat. Appl. DE2453063A1, May 13, 1976.
    Return to citation in text: [1]
  39. Linkies, A.; Reuschling, D. Process for preparing crystalline salts of acetoacetamide-N-sulfofluoride. U.S. Patent US4618455, Oct 21, 1986.
    Return to citation in text: [1]
  40. Appel, R.; Rittersbacher, H. Chem. Ber. 1964, 97, 849–851. doi:10.1002/cber.19640970330
    Return to citation in text: [1]
  41. Appel, R.; Montenarh, M. Chem. Ber. 1976, 109, 2437–2441. doi:10.1002/cber.19761090710
    Return to citation in text: [1]
  42. Beran, M.; Příhoda, J.; Taraba, J. Polyhedron 2010, 29, 991–994. doi:10.1016/j.poly.2009.11.024
    Return to citation in text: [1]
  43. Liu, C.; Shi, S.; Liu, Y.; Liu, R.; Lalancette, R.; Szostak, R.; Szostak, M. Org. Lett. 2018, 20, 7771–7774. doi:10.1021/acs.orglett.8b03175
    Return to citation in text: [1]

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